SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis

Athwal, VS, Pritchett, J ORCID: https://orcid.org/0000-0003-2620-7061, Llewellyn, J, Martin, K, Camacho, E, Raza, SMA, Phythian‐Adams, A, Birchall, LJ, Mullan, AF, Su, K, Pearmain, L, Dolman, G, Zaitoun, AM, Friedman, SL, MacDonald, A, Irving, WL, Guha, IN, Hanley, NA and Piper Hanley, K (2017) SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis. EMBO Molecular Medicine, 9 (12). pp. 1696-1710. ISSN 1757-4676

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Official URL: http://embomolmed.embopress.org/content/9/12/1696

Abstract

Fibrosis and organ failure is a common endpoint for many chronicliver diseases. Much is known about the upstream inflammatorymechanisms provoking fibrosis and downstream potential fortissue remodeling. However, less is known about the transcrip-tional regulationin vivogoverning fibrotic matrix deposition byliver myofibroblasts. This gap in understanding has hamperedmolecular predictions of disease severity and clinical progressionand restricted targets for antifibrotic drug development. In thisstudy, we show the prevalence of SOX9in biopsies from patientswith chronic liver disease correlated with fibrosis severity andaccurately predicted disease progression toward cirrhosis. Inacti-vation ofSox9in mice protected against both parenchymal andbiliary fibrosis, and improved liver function and amelioratedchronic inflammation. SOX9was downstream of mechanosignalingfactor, YAP1. These data demonstrate a role for SOX9in liverfibrosis and open the way for the transcription factor and itsdependent pathways as new diagnostic, prognostic, and therapeu-tic targets in patients with liver fibrosis.

Item Type:	Article (Article)
Peer-reviewed:	Yes
Date Deposited:	10 Nov 2017 16:20
Publisher:	Wiley
Additional Information:	This is an Open Access article published in EMBO Molecular Medicine, published by Wiley, copyright The Author(s).
Divisions:	Faculties > Science and Engineering
Subject terms:	Science & Technology, Life Sciences & Biomedicine, Medicine, Research & Experimental, Research & Experimental Medicine, extracellular matrix, hepatic stellate cells, liver fibrosis, SOX9, YAP1, HEPATIC STELLATE CELLS, TO-MESENCHYMAL TRANSITION, AUTOSOMAL SEX REVERSAL, C VIRUS-INFECTION, SRY-RELATED GENE, CAMPOMELIC DYSPLASIA, TRANSCRIPTION FACTORS, HUMAN PANCREAS, RISK SCORE, BILE-DUCTS, Bile Ducts, Liver, Cells, Cultured, Macrophages, Animals, Mice, Inbred C57BL, Mice, Transgenic, Humans, Mice, Rats, Liver Diseases, Liver Cirrhosis, Disease Models, Animal, Disease Progression, Carbon Tetrachloride, Severity of Illness Index, Signal Transduction, Middle Aged, Female, Male, Hepatic Stellate Cells, SOX9 Transcription Factor, SOX9, YAP1, extracellular matrix, hepatic stellate cells, liver fibrosis, Animals, Bile Ducts, Carbon Tetrachloride, Cells, Cultured, Disease Models, Animal, Disease Progression, Female, Hepatic Stellate Cells, Humans, Liver, Liver Cirrhosis, Liver Diseases, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Rats, SOX9 Transcription Factor, Severity of Illness Index, Signal Transduction, 06 Biological Sciences, 11 Medical And Health Sciences
URI:	https://e-space.mmu.ac.uk/id/eprint/619407
DOI:	https://doi.org/10.15252/emmm.201707860
ISSN	1757-4676

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